A complex interplay of positive and negative signals regulates T cell activation and maintenance of T cell effector function. Members of the TNF ligand/TNF receptor superfamily figure prominently in this matrix of signals, bridging cells of the immune system, as well as with cells of other organ systems. In so doing, TNF superfamily members contribute to both tissue homeostasis and pathogenesis, via effects on cell survival and death, cellular differentiation, and inflammation. From the standpoint of autoimmune pathogenesis, interesting members of the TNF ligand superfamily are TNF-related apoptosis-inducing ligand (TRAIL), and TWEAK (TNF-related weak inducer of apoptosis).
TRAIL binds to a number of different cognate receptors of the TNF receptor superfamily, some leading to triggering of intracellular signaling pathways and others simply acting as decoy receptors. The triggering receptors in humans are TRAIL-R1, TRAIL-R2, and osteoprotegrin, and in mice the sole triggering receptor is DR5. Virtually all cells of the immune system (T lymphocytes, B lymphocytes, natural killer cells, dendritic cells, monocytes, granulocytes) upregulate surface TRAIL and/or release soluble TRAIL stored in secretory vesicles in response to interferon and other activation signals. TRAIL inhibits autoimmunity in several animal models. Evidence for TRAIL's capacity to inhibit experimental autoimmune encephalitis (EAE), a murine model for MS, has come from experiments invoking TRAIL−/−knockout mice, soluble TRAIL receptor (sDR5) or neutralizing anti-TRAIL mAb capable of blocking TRAIL function, and embryonic stem cell-derived dentritic cells co-expressing TRAIL and pathogenic MOG (myelin oligo-dendrocyte glycoprotein peptide). Interestingly, in MS patients, soluble TRAIL has emerged as a response marker for IFN-β therapy, with those most likely to respond to treatment showing early and sustained soluble TRAIL induction after therapy. Yet, TRAIL's impact on MS/EAE may be more complex, for example, the suggestion that TRAIL may promote brain cell apoptosis. Both TRAIL and FasL have been implicated in negative regulation of T cells.
TWEAK and its counter-receptor Fn14 (fibroblast growth factor-inducible 14 kDa protein) are another TNF family ligand-receptor pair expressed in a range of immune and non-immune cell types, including NK cells, macrophages, dendritic cells, microglial cells, glial cells and endothelial cells. TWEAK promotes the proliferation of some cell types (astrocytes, endothelial cells, and certain human tumor cell lines), and suppresses others (erythroblasts, kidney cells, mesangial cells, neuronal cells, NK cells, monocytes), TWEAK stimulates production of various inflammatory cytokines, chemokines and adhesion molecules. However, the TWEAK:Fn14 signaling axis has effects that go beyond cell proliferation and cytokine production. Interestingly, the richer set of functions linked to TWEAK over the years include ones that tie into autoimmunity. TWEAK increases the permeability of the neurovascular unit, and its endogenous expression is elevated in the CNS during EAE and acute cerebral ischemia. Moreover, TWEAK has pro-angiogenic activity, which is of interest given the association between angiogenesis and autoimmune pathogenesis. TWEAK increases EAE severity and associated neurodegeneration. The induction of inhibitory anti-TWEAK or Fn14 Ab, via vaccination with the extracellular domain of either TWEAK or Fn14, ameliorates EAE manifestations in rat and mouse models.
Multiple sclerosis (MS) is a debilitating neurological disease, and despite an expanding set of treatment options, there remains a pressing need for more effective therapeutic agents. While the precise etiology of MS is unknown, key features of its pathogenesis and clinical evolution are emerging. Pathogenic effector T cells are thought to be pivotal in driving the disease, and thus many therapeutic paths are converging on these cells, with goals such as blocking their activation and re-activation, eliminating them from the larger T cell reservoir, and interfering with their transit to sites of pathogenesis within the CNS.
Both the TWEAK/Fn14 and TRAIL/TRAILR signaling axes have been implicated in cancer. See, e.g., “TRAIL receptor signalling and modulation: Are we on the right TRAIL?”, Cancer Treatment Reviews 35 (2009) 280-288; and “The TWEAK-Fn14 cytokine-receptor axis: discovery, biology and therapeutic targeting”, Nature 7 (2008) 411-425.